Methods for treatment of incontinence associated with sexual activity

ABSTRACT

The invention provides compositions and methods for treating incontinence associated with sexual activity.

CROSS REFERENCE TO RELATED APPLICATION

This patent application claims priority pursuant to 35 U.S.C. §119(e) toU.S. Provisional Patent Application Ser. No. 61/507,686 filed Jul. 14,2011, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to methods for treating incontinence usingbotulinum toxins and other treatments.

BACKGROUND

Incontinence associated with sexual activity encompasses several forms,including orgasm-associated incontinence and climacturia, and caninvolve incontinence at different points along the sexual spectrum, forexample, at penetration, during intercourse, or at climax. The conditioncan be associated with disorders including overactive bladder (OAB) andneurogenic detrussor overactivity (NDO), and has received increasingattention in the medical literature. Additionally, it can significantlyimpact sexual satisfaction among both sufferers (both men and women) andtheir partners. Some male sufferers develop incontinence associated withsexual activity following prostate surgery such as radical prostatectomy(RP; removal of the prostate) or brachytherapy.

Prostate cancer is the second most commonly diagnosed cancer in males inthe United States, accounting for approximately 33% of new cancer cases,and is the third leading cause of cancer-related death in men. Severalsurgery-related complications are associated with RP, including urinaryincontinence and sexual dysfunction. The nature and degree of sexualdysfunction can vary widely following RP, including erectiledysfunction, loss of libido, orgasm alterations (anorgasmia, decreasedorgasmic intensity, dysorgasmia and orgasm-associated incontinence) anddecreased sexual satisfaction. Abouassaly and coworkers (Abouassaly R,Lane B. Lakin M, Klein E, Gill I. Ejaculatory incontinence after radicalprostatectomy: a review of 26 cases. Program and abstracts of the SexualMedicine Society of North America Fall Meeting; Nov. 17-20, 2005; NewYork, N.Y. Abstract 1) reported their findings with men who hadclimacturia after having undergone radical prostatectomy. Of anestimated 220 patients evaluated, 26 men experienced urine leak almostexclusively at the time of orgasm. The average age of the patients was62 years. Patients experienced anywhere from 3 to 120 mL of urine leak(by patient self-report) at the time of orgasm. The authors felt thatthe occurrence of ejaculatory incontinence is high enough to beconsidered as part of the routine post-prostatectomy evaluation. In a2006 study of 42 men, two years following RP, 68% reported experiencingclimacteria. Forty-eight percent felt that it was a significant botherto them. In a 2007 study of 475 patients, 20% reported incontinenceassociated with sexual activity following radical pelvic surgery. Menwere more likely to experience it in the first twelve months followingsurgery than later. Common methods of dealing with incontinenceassociated with sexual activity include emptying the bladder before sexand wearing a condom during sex. Thus, improved treatment methods aresought.

Men can also display a form of stress incontinence after RP whereinincontinence can occer during intercourse and continue through climax.

In women, incontinence associated with sexual activity may be associatedwith detrusor overactivity linked to overactive bladder (OAB), or toneurogenic detrussor overactivity (NDO)-one study has found that orgasmcan produce an uninhibited detrusor contraction. It has also beenassociated with female ejaculation in the absence of OAB (Cartwright,2007) or other urodynamic abnormality. Additionally, some researchersspeculate that incontinence associated with sexual activity can belinked with stress or sphincter incontinence. This incontinence can, asin the case with males, occur at any point from before penetration toafter climax.

Coital Incontinence (CI) is urinary leakage that occurs during eitherpenetration or orgasm and can occur with a sexual partner or withmasturbation. It has been reported to occur in 10% to 24% of sexuallyactive women with pelvic floor disorders, yet CI may still be anunderreported problem since sexual or urinary dysfunction may not beoften or readily discussed due to patient or physician embarrassment.Unfortunately, CI can have a disturbing impact on Quality of Life (QoL)and sexuality. Women rarely refer to it spontaneously, with only 3% ofwomen self-reporting sexual disorders including CI; even with directquestioning, only 20% will admit to it. The impact on QoL. from CI issignificant. Sexually active women with CI reported a worse QoL thanthose without it.

Coital incontinence is divided into 2 subtypes based on when urinaryleakage occurs: incontinence with penetration and incontinence withorgasm. Each has different pathophysiologic causes. In the originalseries of 79 patients with CI, two-thirds experienced CI withpenetration, while one-third did so with orgasm. After uro-dynamictesting, CI with penetration was strongly correlated to stress urinaryincontinence, while CI from orgasm was strongly correlated with detrusoroveractivity. A larger, more recent series of 132 women confirms thefindings that the majority of women, 63%, experience CI frompenetration, while 37% do so from orgasm.

Botulinum toxin type A is the most lethal natural biological agent knownto man. About 50 picograms of botulinum toxin type A (available fromAllergan, Inc., of Irvine, Calif under the tradename BOTOX®) is an LD₅₀in mice. One unit (U) of botulinum toxin is defined as the LD₅₀ uponintraperitoneal injection into female Swiss Webster mice weighing 18-20grams each. Seven immunologically distinct botulinum neurotoxins havebeen characterized, these being respectively botulinum neurotoxinserotypes A, B, C₁, D, E, F and G, each of which is distinguished byneutralization with type-specific antibodies. The different serotypes ofbotulinum toxin vary in the animal species that they affect and in theseverity and duration of the paralysis they evoke. The botulinum toxinsapparently bind with high affinity to cholinergic motor neurons, aretranslocated into the neuron and block the release of acetylcholine.

Botulinum toxins have been used in clinical settings for the treatmentof neuromuscular disorders characterized by hyperactive skeletalmuscles. Botulinum toxin type A has been approved by the U.S. Food andDrug Administration for the treatment of blepharospasm, strabismus,hemifacial spasm, cervical dystonia, and migraine headaches. Botulinumtoxin type B has also been approved by the FDA for the treatment ofcervical dystonia. Clinical effects of peripheral intramuscularbotulinum toxin type A are usually seen within one week of injection.The typical duration of symptomatic relief from a single intramuscularinjection of botulinum toxin type A averages about three months.

It has been reported that botulinum toxin type A has been used inclinical settings as follows:

-   -   about 75-125 U (U) of BOTOX® per intramuscular injection        (multiple muscles) to treat cervical dystonia;    -   5-10 U of BOTOX® per intramuscular injection to treat glabellar        lines (brow furrows) (5 U injected intramuscularly into the        procerus muscle and 10 U injected intramuscularly into each        corrugator supercilii muscle);    -   about 30-80 U of BOTOX® to treat constipation by intrasphincter        injection of the puborectalis muscle;    -   about 1-5 U per muscle of intramuscularly injected BOTOX® to        treat blepharospasm by injecting the lateral pre-tarsal        orbicularis oculi muscle of the upper lid and the lateral        pre-tarsal orbicularis oculi of the lower lid.    -   to treat strabismus, extraocular muscles have been injected        intramuscularly with between about 1-5 U of BOTOX®, the amount        injected varying based upon both the size of the muscle to be        injected and the extent of muscle paralysis desired (i.e. the        amount of diopter correction desired).    -   to treat upper limb spasticity following stroke by intramuscular        injections of BOTOX® into five different upper limb flexor        muscles, as follows:        -   (a) flexor digitorum profundus: 7.5 U to 30 U        -   (b) flexor digitorum sublimus: 7.5 U to 30 U        -   (c) flexor carpi ulnaris: 10 U to 40 U        -   (d) flexor carpi radialis: 15 U to 60 U        -   (e) biceps brachii: 50 U to 200 U.

Each of the five indicated muscles has been injected at the sametreatment session, so that the patient receives from 90 U to 360 U ofupper limb flexor muscle BOTOX® by intramuscular injection at eachtreatment session.

To treat migraine, pericranial (symmetrically into glabellar, frontalisand temporalis muscles) injection of BOTOX® has showed significantbenefit as a prophylactic treatment compared to vehicle as measured bydecreased measures of migraine frequency, maximal severity, associatedvomiting and acute medication use over the three month period followingthe 25 U injection.

Additionally, intramuscular botulinum toxin has been used in thetreatment of tremor in patients with Parkinson's disease, although ithas been reported that results have not been impressive. Marjama-Jyons,J., et al., Tremor-Predominant Parkinson's Disease, Drugs & Aging 16(4);273-278:2000.

In addition to having pharmacologic actions at the peripheral location,botulinum toxins may also have inhibitory effects in the central nervoussystem. Work by Weigand et al., Naunyn-Schmiedeberg's Arch. Pharmacol.1976; 292, 161-165, and Habermann, Naunyn-Schmiedeberg's Arch.Pharmacol. 1974; 281, 47-56 showed that botulinum toxin is able toascend to the spinal area by retrograde transport.

A Botulinum toxin has also been proposed for the treatment ofrhinorrhea, hyperhydrosis and other disorders mediated by the autonomicnervous system (U.S. Pat. No. 5,766,605), tension headache, (U.S. Pat.No. 6,458,365), migraine headache (U.S. Pat. No. 5,714,468),post-operative pain and visceral pain (U.S. Pat. No. 6,464,986), paintreatment by intraspinal toxin administration (U.S. Pat. No. 6,113,915),Parkinson's disease and other diseases with a motor disorder component,by intracranial toxin administration (U.S. Pat. No. 6,306,403), hairgrowth and hair retention (U.S. Pat. No. 6,299,893), psoriasis anddermatitis (U.S. Pat. No. 5,670,484), injured muscles (U.S. Pat. no.6,423,319, various cancers (U.S. Pat. No. 6,139,845), pancreaticdisorders (U.S. Pat. No. 6,143,306), smooth muscle disorders (U.S. Pat.No. 5,437,291, including injection of a botulinum toxin into the upperand lower esophageal, pyloric and anal sphincters)), prostate disorders(U.S. Pat. No. 6,365,164), inflammation, arthritis and gout (U.S. Pat.No. 6,063,768), juvenile cerebral palsy (U.S. Pat. No. 6,395,277), innerear disorders (U.S. Pat. No. 6,265,379), thyroid disorders (U.S. Pat.No. 6,358,513), parathyroid disorders (U.S. Pat. No. 6,328,977).Additionally, controlled release toxin implants are known (see e.g. U.S.Pat. Nos. 6,306,423 and 6,312,708).

Adrenergic nerves release norepinephrine as the neurotransmitter for thesympathetic nervous system. The sympathetic system activates andprepares the body for vigorous muscular activity, stress, andemergencies. Adrenergic drugs stimulate the adrenergic nerves directlyby mimicking the action of norepinephrine or indirectly by stimulatingthe release of norepinephrine. An adrenergic agent is a drug, or othersubstance, which has effects similar to, or the same as, epinephrine(adrenaline). Thus, it is a kind of sympathomimetic agent.Alternatively, it may refer to something which is susceptible toepinephrine, or similar substances, such as a biological receptor(specifically, the adrenergic receptors).

Adreneric agonists stimulate a response from the adrenergic receptors.The five categories of adrenergic receptors are: α₁, α₂, β₁, β₂, and β₃,and agonists vary in specificity between these receptors, and may beclassified respectively. However, there are also other mechanisms ofadrenergic agonism. Epinephrine and norepinephrine are endogenous andbroad-spectrum. More selective agonists are more useful in pharmacology.

A great number of drugs are available which can affect adrenergicreceptors. Each drug has its own receptor specificity giving it a uniquepharmacological effect. Other drugs affect the uptake and storagemechanisms of adrenergic catecholamines, prolonging their action. Agentsthat work with and activate the adrenergic receptors include alpha- andbeta-adrenergic agonists. Agents that increase neurotransmission inendogenous chemicals such as epinephrine and norepinephrine includeamphetamines, cocaine, methylenedioxymethamphetamine (MDMA), tyramine,nicotine, caffeine, and methylphenidate. Agents that exhibit aspects ofboth of these modes include ephedrine and pseudoephedrine.

Adequate treatments for incontinence associated with sexual activity arecurrently lacking, therefore long-lasting, minimally invasive methods oftreatment are desirable.

SUMMARY

Embodiments of the invention include methods of treating incontinence,including urinary incontinence, associated with sexual activity using abotulinum toxin. In embodiments the incontinence treatment can comprisetreatment of females with climacturia who also have detrusoroveractivity, such as, for example, OAB, or NDO, or the like. Inembodiments, the OAB or NDO can be state-dependent, i.e. onlypresent at,for example, penetration, or orgasm, or the like. In embodiments theincontinence treatment can comprise treatment of females withclimacturia who also have stress incontinence. In certain embodimentsthe incontinence treatment can comprise treatment of females withclimacturia who do not also have demonstrated bladder or outletdisorders. In certain embodiments the incontinence treatment cancomprise treatment of males who do not also have demonstrated bladder oroutlet disorders. In embodiments the incontinence can occur before,during, or after orgasm. In embodiments the incontinence can occurbefore, during, or after penetration. In embodiments, the botulinumtoxin is administered to, for example, the bladder, or the like. Inembodiments the toxin is administered, for example, via injection, ortransdermally, or via instillation, or the like.

Embodiments include a method of treating post-surgical incontinenceassociated with sexual activity comprising administering atherapeutically effective amount of a botulinum toxin to a patient inneed thereof, thereby treating the incontinence associated with sexualactivity. In embodiments the incontinence associated with sexualactivity occurs following a surgical procedure, such as, for example,for a prostate disorder. In embodiments the surgical procedure isselected from the group consisting of radical prostatectomy,laparoscopic radical prostatectomy, transurethral resection of theprostate, transurethral microwave therapy, transurethral needleablation, and cryosurgery. In embodiments, the botulinum toxin isadministered to, for example, the prostate, the bladder, or acombination thereof, or the like. In embodiments the toxin isadministered, for example, via injection, or transdermally, or viainstillation, such as into the bladder, or the like. In embodiments theincontinence can occur before, during, or after orgasm. In embodimentsthe incontinence can occur before, during, or after penetration.

Embodiments include a method of preventing post-surgical incontinenceassociated with sexual activity comprising administering atherapeutically effective amount of a botulinum toxin to a patient inneed thereof, thereby preventing the incontinence associated with sexualactivity. In embodiments the incontinence associated with sexualactivity occurs following a surgical procedure, such as, for example,for a prostate disorder. In embodiments the surgical procedure isselected from the group consisting of radical prostatectomy,laparoscopic radical prostatectomy, transurethral resection of theprostate, transurethral microwave therapy, transurethral needleablation, and cryosurgery. In embodiments, the botulinum toxin isadministered to, for example, the prostate, the bladder, or acombination thereof, or the like. In embodiments the toxin isadministered, for example, via injection, or transdermally, or viainstillation, such as into the bladder, or the like. In embodiments thepatient is administered the botulinum toxin at a time selected from thegroup consisting of before surgery, during surgery, after surgery, andcombinations thereof. In embodiments the incontinence can occur before,during, or after orgasm. In embodiments the incontinence can occurbefore, during, or after penetration.

In embodiments of the invention the botulinum toxin is selected from thegroup consisting of types A, B, C, D, E, and, G.

Embodiments of the invention include methods of treating incontinence,including urinary incontinence, associated with sexual activity using abotulinum toxin in combination with, for example, a drug that has aneffect on the tonicity of the bladder or sphincter muscle, such as theurinary sphincter. In embodiments the incontinence treatment cancomprise treatment of females with climacturia who also have detrusoroveractivity, such as, for example, OAB, or NDO, or the like. Inembodiments, the OAB or NDO can be state-dependent, i.e. onlypresent at,for example, penetration, or orgasm, or the like. In embodiments theincontinence treatment can comprise treatment of females withclimacturia who also have stress incontinence. In certain embodimentsthe incontinence treatment can comprise treatment of females withclimacturia who do not also have demonstrated bladder or outletdisorders. In certain embodiments the incontinence treatment cancomprise treatment of males who do not also have demonstrated bladder oroutlet disorders. In embodiments the incontinence can occur before,during, or after orgasm. In embodiments the incontinence can occurbefore, during, or after penetration. In embodiments, the botulinumtoxin in combination with a drug that has an effect on the tonicity of athe sphincter muscle is administered to, for example, the bladder, orthe like. In embodiments the toxin is administered, for example, viainjection, or transdermally, or via instillation, or the like.

Embodiments of the invention include methods of treating incontinence,including urinary incontinence, associated with sexual activity using adrug that has an effect on the tonicity of the bladder or sphinctermuscle, such as the urinary sphincter. In embodiments the incontinencetreatment can comprise treatment of females with climacturia who alsohave detrusor overactivity, such as, for example, OAB, or NDO, or thelike. In embodiments, the OAB or NDO can be state-dependent, i.e.onlypresent at, for example, penetration, or orgasm, or the like. Inembodiments the incontinence treatment can comprise treatment of femaleswith climacturia who also have stress incontinence. In certainembodiments the incontinence treatment can comprise treatment of femaleswith climacturia who do not also have demonstrated bladder or outletdisorders. In certain embodiments the incontinence treatment cancomprise treatment of males who do not also have demonstrated bladder oroutlet disorders. In embodiments the incontinence can occur before,during, or after orgasm. In embodiments the incontinence can occurbefore, during, or after penetration. In embodiments, the botulinumtoxin in combination with a drug that has an effect on the tonicity of athe sphincter muscle is administered to, for example, the bladder, orthe like. In embodiments the toxin is administered, for example, viainjection, or transdermally, or via instillation, or the like.

In embodiments the drug that has an effect on the tonicity of thesphincter muscle can be, for example, an anticholinergic, or anandergenic, such as an alpha- or beta-adrenergic agonist, oramphetamines, cocaine, methylenedioxymethamphetamine (MDMA), tyramine,nicotine, caffeine, and methylphenidate. In embodiments the drug thathas an effect on the tonicity of the bladder or sphincter muscle can beany drug that relaxes smooth muscles in the gastrointestinal tract, orrelaxes bladder muscles, or increases contraction of the bladdersphincter. For example, SUDAFED® contains the active ingredientpseudoephedrine and refers to a family of over the counter (OTC)decongestants manufactured by McNeil Laboratories (a division of Johnson& Johnson) for sale in Australia, New Zealand, Canada, Ireland, SouthAfrica, the United Kingdom, and the United States. The drug exhibits ananticholinergic effect and thus is suitable for use in embodiments ofthe invention. Other anticholinergics suitable for use in embodiments ofthe invention include oxybutynin (Ditropan), tolterodine (Detrol),darifenacin (Enablex), fesoterodine (Toviaz), solifenacin (Vesicare) andtrospium (Sanctura).

Other drugs that can be used in embodiments of the present inventioninclude Imipramine and Duloxetine.

DESCRIPTION OF EXEMPLARY EMBODIMENTS

The present invention meets this need and provides for improved methodsfor treating incontinence associated with sexual activity. In someembodiments, the methods comprise the step of locally administering aneurotoxin (e.g., a botulinum toxin type A and/or other types) to atleast one anatomical site. In some embodiments, the dose of neurotoxinto be administered is equivalent to about 1 U to about 500 U of abotulinum toxin type A. In certain embodiments, the method ofadministration can be systemic, such as, for example, intravenously, orlocal, such as, for example, via injection into the prostate or bladderor a combination thereof, by implant, with a topical formulation, viainstillation, or the like.

In one aspect, the invention comprises a method of treating incontinenceassociated with sexual activity in patients who also have detrusoroveractivity, such as, for example, OAB, or NDO, or the like, comprisingadministering an effective amount of a botulinum toxin composition tothe surface or within the tissue of a patient in need thereof. Incertain embodiments, for example, the botulinum toxin compositioncomprises botulinum toxin encapsulated in phospholipid micelles, and/orone or more primary stabilizers, and/or one or more skin penetrationenhancers. In an example, 50 U, or 75 U, or 100 U, or 150 U, or 200 U,or 300 U, or 400 U of botulinum toxin type A is instilled into thebladder of a patient suffering from incontinence associated with sexualactivity wherein the patient also suffers from detrusor overactivity. Inalternate embodiments, 50 U, or 75 U, or 100 U, or 150 U, or 200 U, or300 U, or 400U of botulinum toxin type A is injected into the bladder ofa patient suffering from incontinence associated with sexual activitywherein the patient also suffers from detrusor overactivity.

In one aspect, the invention comprises a method of treatingpost-surgical incontinence associated with sexual activity, such as, forexample, following RP, comprising administering an effective amount of abotulinum toxin composition to the surface or within the tissue of apatient in need thereof. In certain embodiments, for example, thebotulinum toxin composition comprises botulinum toxin encapsulated inphospholipid micelles, and/or one or more primary stabilizers, and/orone or more skin penetration enhancers. In certain embodiments, forexample, such treatment can comprise administration of a botulinum totoxin to the prostate via, for example, injection, topical admistration,or the like.

In one aspect, the invention comprises a method of preventingpost-surgical incontinence associated with sexual activity, such as, forexample, following RP, comprising administering an effective amount of abotulinum toxin composition to the surface or within the tissue of apatient in need thereof. In certain embodiments, for example, thebotulinum toxin composition comprises botulinum toxin encapsulated inphospholipid micelles, and/or one or more primary stabilizers, and/orone or more skin penetration enhancers. In certain embodiments, forexample, such treatment can comprise administration of a botulinum totoxin to the prostate via, for example, injection, topical admistration,or the like.

DEFINITIONS

The following definitions apply herein.

“About” means plus or minus ten percent of the value so qualified.

“Alleviating” means a reduction in or prevention of the occurrence of asymptom related to incontinence associated with sexual activty. Thus,alleviating includes some reduction, significant reduction, near totalreduction, and total reduction of a symptom related to incontinenceassociated with sexual activty. An alleviating effect may not appearclinically for between 1 and 7 days after administration of a botulinumtoxin to a patient.

“Botulinum toxin” means a botulinum neurotoxin as either pure toxin(i.e. about 150 kDa weight molecule) or as a complex (i.e. about 300 toabout 900 kDa weight complex comprising a neurotoxin molecule and one ormore associated non-toxic molecules), and excludes botulinum toxinswhich are not neurotoxins such as the cytotoxic botulinum toxins C2 andC3, but includes recombinantly made, hybrid, modified, and chimericbotulinum toxins.

“Drug that has an effect on the tonicity of the bladder or sphinctermuscle” means any drug, compound, or molecule that can affect the muscletension of the bladder or a sphincter muscle, such as the urinarysphincter.

“Effective amount” as applied to the neurotoxin means that amount of theneurotoxin generally sufficient to effect a desired change in thesubject. In some embodiments, the neurotoxin can be administered in anamount between about 0.01 U/kg and about 35 U/kg and the symptoms of thecondition can be substantially alleviated for between about 1 month andabout 27 months, for example for from about 1 month to about 6 months.

“Improved patient function” means an improvement measured by factorssuch as reduced pain, reduced time spent in bed, reduced urination uponclimax, increased ambulation, healthier attitude, more varied lifestyleand/or healing permitted by normal muscle tone. Improved patientfunction is synonymous with an improved quality of life (QoL). QoL canbe assessed using, for example, the known SF-12 or SF-36 health surveyscoring procedures. SF-36 assesses a patient's physical and mentalhealth in the eight domains of physical functioning, role limitationsdue to physical problems, social functioning, bodily pain, generalmental health, role limitations due to emotional problems, vitality, andgeneral health perceptions. Scores obtained can be compared to publishedvalues available for various general and patient populations.

“Incontinence” means the unintended release of bodily fluid, not limitedto urine.

“Incontinence associated with sexual activity” means the unintendedrelease of bodily fluid, not limited to urine, during sexual activity.

“Locally administering” or “local administration” means directadministration to a location, such as, for example, by injection,instillation, implant, or topical application, such as, for example,using microemulsion creams or topical compositions. Local administrationexcludes systemic routes of administration, such as intravenous or oraladministration.

“Sexual activity” means any act relating to sex, including, for example,foreplay, penetration, intercourse, oral sex, etc.

“Treating” means to alleviate (or to eliminate) at least one symptomrelated to climacturia, such as incontinence, either temporarily orpermanently.

“Urogenic abnormality” means any condition causing a urologic effect,such as OAB, NDO, stress incontinence, sphincter incontinence, etc.

The pharmaceutical compositions contemplated by this invention includepharmaceutical compositions suited for topical and local action.

In some embodiments the term “topical” as employed herein relates to theuse of a composition, as described herein, incorporated in a suitablepharmaceutical carrier. Accordingly, such topical compositions includethose pharmaceutical forms in which the compound is applied externallyby direct contact with the skin surface to be treated. Conventionalpharmaceutical forms for this purpose include ointments, liniments,creams, shampoos, lotions, pastes, jellies, sprays, aerosols, and thelike, and can be applied in patches or impregnated dressings dependingon the part of the body to be treated. The term “ointment” embracesformulations (including creams) having oleaginous, water-soluble andemulsion-type bases, e.g., petrolatum, lanolin, polyethylene glycols, aswell as mixtures of these. In some embodiments, the term “topical” asemployed herein relates to the use of a composition suitable forinstillation, a procedure in which a fluid is introduced into a cavityor passage of the body and allowed to remain for a specific length oftime before being drained or withdrawn. It is performed to expose thetissues of the area to the solution, to warmth or cold, or to a drug orsubstance in the solution. In some embodiments, the composition can bewarmed or cooled prior to instillation.

The compositions can be applied a single time or repeatedly at regularor non-regular intervals for a sustained period of time. In certainembodiments, compositions of the invention can be administered topicallyto the part of the body to be treated. In certain embodiments,compositions of the invention can be administered systemically, such as,for example, intravenously.

For topical use, the compositions can be formulated in aqueoussolutions, creams, ointments or oils exhibiting physiologicallyacceptable osmolarity by addition of pharmacologically acceptablebuffers and salts. Such formulations may or may not, depending on thedispenser, contain preservatives such as benzalkonium chloride,chlorhexidine, chlorobutanol, parahydroxybenzoic acids andphenylmercuric salts such as nitrate, chloride, acetate, and borate, orantioxidants, as well as additives like EDTA, sorbitol, boric acid etc.as additives. Furthermore, particularly aqueous solutions may containviscosity increasing agents such as polysaccharides, e.g.,methylcellulose, mucopolysaccharides, e.g., hyaluronic acid andchondroitin sulfate, or polyalcohol, e.g., polyvinylalcohol. Variousslow releasing gels and matrices may also be employed as well as solubleand insoluble ocular inserts, for instance, based on substances formingin-situ gels. Depending on the actual formulation and compound to beused, various amounts of the drug and different dose regimens may beemployed.

The neurotoxins of the instant invention can be administered by anysuitable means. In an embodiment of the invention, botulinum toxin isadministered by injection. Such injection can be administered to anyaffected area. For example, the neurotoxin can be injectedurethroscopically into the prostate with, for example, 100 U with singleor serial dosing, or 200 U with single or serial dosing, or 300 U withsingle or serial dosing, or 400 U with single or serial dosing, or thelike. In certain embodiments, the neurotoxin is injected every threeweeks, or every four weeks, or every five weeks, or a lesser or greaterinterval, or the like until a therapeutic effect is achieved, or up toabout 2500 U, or up to about 3000 U, or up to about 3500 U, or more, orthe like.

Botulinum toxins for use according to the present invention can bestored in lyophilized, vacuum dried form in containers under vacuumpressure or as stable liquids. Prior to lyophilization the botulinumtoxin can be combined with pharmaceutically acceptable excipients,stabilizers and/or carriers, such as albumin. The lyophilized materialcan be reconstituted with saline or water to create a solution orcomposition containing the botulinum toxin to be administered to thepatient.

Exemplary, commercially available, botulinum toxin containingcompositions include, but are not limited to, BOTOX® (botulinum toxintype A neurotoxin complex with human serum albumin and sodium chloride)available from Allergan, Inc., of Irvine, Calif. in 100 U vials as alyophilized powder to be reconstituted with 0.9% sodium chloride beforeuse), DYSPORT® (Clostridium botulinum type A toxin haemagglutinincomplex with human serum albumin and lactose in the formulation,available from Ipsen Limited, Berkshire, U.K. as a powder to bereconstituted with 0.9% sodium chloride before use) which can be used atabout 3 to about 4 times the amounts of BOTOX® as set forth herein ineach instance, and MYOBLOC® (an injectable solution comprising botulinumtoxin type B, human serum albumin, sodium succinate, and sodium chlorideat about pH 5.6, available from Solstice Neurosciences, Inc., South SanFrancisco, Calif.) which can be used at about 30 to about 50 times theamounts of BOTOX® as set forth herein in each instance, as known in theart. XEOMIN® (a 150 kDa botulinum toxin type A formulation availablefrom Merz Pharmaceuticals, Potsdam, Germany) is another usefulneurotoxin which can be used at about 1 to about 2 times the amounts ofBOTOX® as set forth herein in each instance.

In additional embodiments, no less than about 10 U and no more about 400U of BOTOX®; or no less than about 30 U and no more than about 1600 U ofDYSPORT®; or no less than about 250 U and no more than about 20000 U ofMYOBLOC® are administered per site, per patent treatment session.

In still further embodiments, no less than about 20 U and no more thanabout 300 U of BOTOX®; or no less than about 60 U and no more than about1200 U of DYSPORT®; or no less than about 1000 U and no more than about15000 U of MYOBLOC® are administered per site, per patent treatmentsession.

Although the composition may only contain a single type of botulinumtoxin, such as, for example, type A, as the active ingredient, othertherapeutic compositions may include two or more types of botulinumtoxins. For example, a composition administered to a patient may includebotulinum toxin type A and botulinum toxin type B, or the like.Administering a single composition containing two different neurotoxinscan permit the effective concentration of each of the neurotoxins to belower than if a single neurotoxin is administered to the patient whilestill achieving the desired therapeutic effects. The compositionadministered to the patient may also contain other pharmaceuticallyactive ingredients, such as, for example, protein receptor or ionchannel modulators, or the like, in combination with the neurotoxin orneurotoxins.

In certain embodiments, compositions of the invention can comprisere-targeted endopeptidases; molecules derived by replacing thenaturally-occurring binding domain of a clostridial toxin with atargeting domain showing a selective binding activity for anon-clostridial toxin receptor present in a cell of interest. Suchmodifications to the binding domain result in a molecule that is able toselectively bind to a non-clostridial toxin receptor present on thetarget cell. A re-targeted endopeptidase can bind to a target receptor,translocate into the cytoplasm, and exert its proteolytic effect on theSNARE complex of the neuronal or non-neuronal target cell of interest.In certain embodiments of the invention, the composition can comprisere-targeted endopeptidases.

Re-targeted endopeptidases can decrease the effects of sensoryafferents, including conditions that are predominantly motor in origin.See, for example, U.S. Pat. No. 7,658,933 to Foster et al., titled“Non-Cytoxtoxic Protein Conojugates”; U.S. Pat. No. 7,659,092 to Fosteret al., titled “Fusion Proteins”; and U.S. application Ser. No.12/303,078 to Foster et al., titled “Treatment of Pain,” allincorporated entirely by reference. In addition, endopeptidases canmodulate pain associated with multiple medical conditions.

Certain embodiments of the invention can utilize a combination ofre-targeted endopeptidases and botulinum toxins. The combination ofbotulinum toxins and re-targeted endopeptidases allows for dosereduction of active agents (with associated reduction in side effects)as well as possible synergistic effects. Non-paralytic effects, and alsopossible prophylactic effects especially when used early in thecondition can provide further benefits. The molar ratio of botulinumtoxin to re-targeted endopeptidases in the combination treatment can be,for example, a 1:1 ratio; a 1:2 ratio; a 1:5 ratio; a 1:10 ratio; a 1:20ratio; a 1:50 ratio; a 1:100 ratio; 1:200 ratio; a 1:500 ratio; a 1:1000ratio; 1:2,000 ratio; a 1:5,000 ratio; a 1:10,000 ratio, or the like. Incertain embodiments the molar ratio of botulinum toxin to re-targetedendopeptidases in the combination treatment can be, for example, a 1:1ratio; a 2:1 ratio; a 5:1 ratio; a 10:1 ratio; a 20:1 ratio; a 50:1ratio; a 100:1 ratio; 200:1 ratio; a 500:1 ratio; a 1000:1 ratio; 2000:1ratio; a 5000:1 ratio; a 10,000:1 ratio, or the like.

Certain embodiments of the invention can utilize an implant foradministration. Implants useful in practicing the methods disclosedherein may be prepared by mixing a desired amount of a stabilizedBotulinum toxin (such as non-reconstituted BOTOX®) or re-targetedendopeptidases into a solution of a suitable polymer dissolved inmethylene chloride. The solution can be prepared at room temperature.The solution can then be transferred to a Petri dish and the methylenechloride evaporated in a vacuum desiccator. Depending upon the implantsize desired and hence the amount of incorporated neurotoxin orre-targeted endopeptidases, a suitable amount of the driedneurotoxin-incorporating implant is compressed at about 8000 p.s.i. for5 seconds or at 3000 p.s.i. for 17 seconds in a mold to form implantdiscs encapsulating the neurotoxin. See e.g. Fung L. K. et al.,Pharmacokinetics of Interstitial Delivery of Carmustine4-Hydroperoxycyclophosphamide and Paclitaxel From a BiodegradablePolymer Implant in the Monkey Brain, Cancer Research 58;672-684:1998.Embodiments of the invention can also utilize botulinum toxins in powderform, and or administered via a needleless injection system, or thelike.

In certain embodiments, administration of the composition can follow,accompany, or precede a surgical procedure, such as, for example,radical prostatectomy, laparoscopic radical prostatectomy, transurethralresection of the prostate, transurethral microwave therapy,transurethral needle ablation, cryosurgery, and the like.

Additionally, in some embodiments, a physician can alter dosage in eachcase in accordance with the assessment of the severity of the condition,as typically done when treating patients with a condition/disorder.Further, in some embodiments, the treatment may have to be repeated atleast one additional time, in some cases several times, depending on theseverity of the condition and the patient's overall health. If, forexample, a patient is not deemed physically suitable for a fulladministration of botulinum toxin, or if a full administration is notdesired for any reason, smaller doses on multiple occasions may prove tobe efficacious.

Of course, an ordinarily skilled medical provider can determine theappropriate dose and frequency of administration(s) to achieve anoptimum clinical result. That is, one of ordinary skill in medicinewould be able to administer the appropriate amount of the toxin, forexample botulinum toxin type A, at the appropriate time(s) toeffectively treat the disorder. The dose of the neurotoxin to beadministered depends upon a variety of factors, including the severityof the disorder. The dose of the toxins employed in accordance with thisinvention may be equivalent to the dose of BOTOX® used in accordancewith the present invention described herein. In various methods of thepresent invention, from about 0.01 U/kg (U of botulinum toxin perkilogram of patient weight) to about 15 U/kg, of a BOTOX® e.g. botulinumtoxin type A, can be administered. In some embodiments, about 0.1 U/kgto about 20 U/kg of BOTOX® may be administered. Use of from about 0.1U/kg to about 30 U/kg of a BOTOX®, is within the scope of a methodpracticed according to the present disclosed invention. In oneembodiment, about 0.1 U/kg to about 150 U/kg botulinum toxin, forexample type A, may be administered.

Significantly, a method within the scope of the present invention canprovide improved patient function.

The botulinum toxin composition can be administered at, for example, adose of 10 to 1000 U of botulinum toxin per affected site, or a dose of20 to 800 U of botulinum toxin per affected site, or a dose of 50 to 500U of botulinum toxin per affected site, or a dose of 100 to 400 U ofbotulinum toxin per affected site, or a dose of 200 to 300 U ofbotulinum toxin per affected site, or the like.

In some embodiments, the affected area can comprise multiple toxinadministration sites.

Suitable active ingredients for inclusion in the composition includebotulinum toxin type A, type B, type C, type D, type E, type F, and typeG. Other active ingredients can include, but are not limited toandrogens, androstenediol and androisoxazole (for anabolic disorders),testosterone (hypogonadism, muscle wasting, male impotence,postmenopausal symptoms in women), dehydrotestosterdne (hypogdnadism,muscle wasting), dehydroepiandrostenone (muscle wasting, fat reduction,fitness); estrogens (postmenopausal symptoms, birth control), 17betaestradiol, estradiol-3,17-diacetate, estradiol-3-acetate,estradiol-17-acetate, estradiol-3, 17-valerate, estradiol-3-valerate,estradio1-17-valerate, ethinyl estradiol, estrone; progesterones(prevent endometriosis, prevent endometrial cancer, control habitualabortion, suppress or synchronize estrus, promote hair growth),progesterone (preg-4-ene-3,20-dione), norethindrone, norgestrieone,norgestadienone, norgestrel, norgestimate, progestogenic acid,dihydroprogesterol, nomagesterol. The testosterone hormone may be usedin any of its usual forms, such as, acetate, propionate,17-beta-cyclopentanepropionate, enanthanate, isobutyrate, undeconate,and the like. Similarly, the estradiols may additionally be used in anyof the known or newly developed forms, such as, for example, pivalate,propionate, cypionate, benzoate and other esters.

In certain embodiments, compositions of the invention can include agentsthat promote healing. For example, vasodilators, such as nitroglycerinand glycerin mononitrate can be encapsulated in a phospholipid micelleand then combined with collagen and/or elastin in a lotion or creamformulation and applied to the skin. Without being limited by theexplanation, it is thought that the formulation of vasodilators in thecomposition enhances the rate of penetration as compared toadministration via, for example, a skin patch. Inclusion of hydrogenperoxide and/or a perfluorocarbon may further enhance oxygenation andhealing.

The composition can contain a single active ingredient or multipleactive ingredients in the same composition. Various combinations ofactive ingredients are contemplated for inclusion in the composition.

Skin or mucus membrane penetration enhancers that promote the absorptionof an active ingredient by the skin or mucus membrane can also beincluded in the composition. Examples of skin or mucus membranepenetration enhancers include, but are not limited to, alcohols, such asshort chain alcohols, long chain alcohols, or polyalcohols, amines andamides, such as urea, amino acids or their esters, amides, AZONE®,derivatives of AZONE®, pyrrolidones, or derivatives of pyrrolidones;terpenes and derivatives of terpenes; fatty acids and their esters;macrocyclic compounds; tensides; or sulfoxides such as,decylmethylsulfoxide. Liposomes, transfersomes, lecithin vesicles,ethosomes, water surfactants, such as anionic, cationic, and nonionicsurfactants, polyols, and essential oils can also function as skin ormucus membrane penetration enhancers.

Embodiments of the invention can comprise micelles, such as, forexample, phospholipid micelles. In certain embodiments, the phospholipidmicelles may comprise sphingosine and cerebroside, for example, or thelike. In some embodiments the primary stabilizers may comprise elastinand collagen, for example, or the like. In some embodiments, the one ormore skin penetration enhancers can be selected from the group thatincludes, for example, d-limonene, allantoin, fulvic acid, myrrh,hydroquinone glyquin, quillaja saponaria (QTS), acanthophyllumsquarrusom (ATS), either singularly or in combination, or the like.

In an embodiment, the botulinum toxin composition comprises:

-   -   approximately 1 to 40% w/w collagen;    -   approximately 1 to 40% w/w elastin;    -   approximately 0.1 to 15% w/w sphingosine phospholipid; and    -   approximately 0.1 to 15% w/w cerebroside phospholipid.

The composition may also be used for topical administration in a formatwhereby the composition penetrates the skin and transdermally denervatesan underlying muscle.

The composition may include d-limonene to enhance penetration of theactive ingredient through the dermal layer. Limonene hasbeen found to bean effective skin penetration enhancer at 0.30%, enhancing skinpermeation of botulinum toxin Type A approximately fourfold.

Quillaja saponaria (QTS) and Acanthophyllum squarrusom (ATS) totalsaponins are two natural skin penetration enhancers that may also beincluded in the composition. They demonstrate moderate activity as skinpenetration enhancers.

Allantoin may also be included in the composition. Allantoin acts as askin protectant and a mild neutral skin penetration enhancer.

Eldopaque or hydroquinone glyquin may also be included as skinpenetration enhancers.

In certain embodiments, the use of collagen in the composition, incombination with elastin and a mixture of sphingosine and cerebroside,maintains the integrity of the complex without denaturing orfragmentation or detoxification. Thus, botulinum toxin can be stabilizedand the stabilized toxin can be successfully delivered transdermally toachieve similar results to those obtained by intramuscular injection ofbotulinum toxin.

Additional components can be included to formulate the composition intoother formats, such as a cream, lotion, spray, mask, gel, etc., that issuitable for topical administration. If formulated as a cream or asolution, the composition should contain the active ingredient insufficiently concentrated quantities in order that the composition doesnot drip off the area of administration.

A preferred method for preparing a stabilized botulinum toxincomposition for topical application below. Briefly, equal amounts ofcollagen and elastin are solubilized in saline. In a separate flask,equal amounts of sphingosine and cerebroside are dissolved in alcohol.The alcohol is then removed. Botulinum toxin A is dissolved in salineand then added to the flask and the flask is swirled to coat thebotulinum toxin protein with a phospholipid micelle coating. Thissolution is then added to the solution of collagen and elastin. Thismethod can be used to prepare compositions containing other types ofbotulinum toxin.

The composition may also be provided on a patch that is adhesivelysecured to the skin so that the active ingredient, such as botulinumtoxin, can pass from the patch through the skin.

Any feature or combination of features described herein are includedwithin the scope of the present invention provided that the featuresincluded in any such combination are not mutually inconsistent as willbe apparent from the context, this specification, and the knowledge ofone of ordinary skill in the art.

It is known that botulinum toxin type A can have an efficacy for up to12 months (European J. Neurology 6 (Supp 4): S111-S1150:1999), and insome circumstances for as long as 27 months (The Laryngoscope109:1344-1346:1999). However, the usual duration of an intramuscularinjection of botulinum type A is typically about 3 to 4 months.

EXAMPLES Example 1

A 62 year old man complains of incontinence associated with sexualactivity after a radical prostatectomy procedure. Based on a thoroughexamination, his doctor recommends a course of botulinum type Ainjections to the bladder wall.

The patient is injected with 200 U of botulinum type A divided among 30injections into the bladder wall. Within 7 days of receiving theinjections, the patient reports the elimination of the incontinencesymptoms.

Example 2

A 41 year old man complains of urinary incontinence at climax. Based ona thorough examination, his doctor recommends botulinum type Aadministration to the bladder wall.

The bladder of the patient is instilled with a solution containing 1000U of botulinum type A by filling the bladder with the solution, allowingthe solution to remain within the bladder for 10 minutes, then drainingthe solution. Within 7 days of receiving the botulinum administration,the patient reports the elimination of the incontinence symptoms.

Example 3

A 44 year old man complains of urinary incontinence at penetration afterurogenital surgery. Based on a thorough examination, his doctorrecommends a series of botulinum type A injections to the prostate.

The prostate of the patient is injected with 100 U of botulinum at 7-dayintervals for 3 weeks. Following the course of injections, the patient'sincontinence symptoms are reduced. Specifically, the volume of urineproduced at climax is reduced.

Example 4

A 24 year old woman complains of incontinence at penetration. She haspreviously been diagnosed with detrussor overactivity. Based on athorough examination, her doctor recommends a series of botulinum type Ainjections to the bladder.

The patient is injected with 400 U of botulinum type B divided among 30injections into the bladder wall. Within 7 days of receiving theinjections, the patient reports the elimination of her incontinencesymptoms.

Example 5

A 61 year old woman complains of incontinence at climax. She has notbeen diagnosed with any urological abnormality. Based on a thoroughexamination, her doctor recommends administration of botulinum type Aadministration to the bladder wall.

The bladder of the patient is instilled with a solution containing 1000U of botulinum type A by filling the bladder with the solution, allowingthe solution to remain within the bladder for 10 minutes, then drainingthe solution. Within 7 days of receiving the botulinum administration,the patient reports the elimination of the incontinence symptoms.

Example 6

A 29 year old man complains of urinary incontinence associated withsexual activity after brachytherapy for prostate cancer. Based on athorough examination, his doctor recommends a course of botulinum type Ainjections to the bladder wall.

The patient is injected with 200 U of botulinum type A divided among 30injections into the bladder wall. Within 7 days of receiving theinjections, the patient reports the elimination of the incontinencesymptoms.

Example 7

A 55 year old man complains of urinary incontinence associated withsexual activity after radiation therapy for prostate cancer. Based on athorough examination, his doctor recommends a course of botulinum type Ainjections to the bladder wall.

The patient is injected with 200 U of botulinum type A divided among 30injections into the bladder wall. Within 7 days of receiving theinjections, the patient reports the elimination of the incontinencesymptoms.

Example 8

A 39 year old man complains of urinary incontinence associated withsexual activity after brachytherapy for prostate cancer. Based on athorough examination, his doctor recommends a treatment of SUDAFED®.

The patient ingests 2 tablets of SUDAFED® each day. Within 7 days ofbeginning the treatment, the patient reports the elimination of theincontinence symptoms.

Example 9

A 55 year old man complains of urinary incontinence associated withsexual activity after radiation therapy for prostate cancer. Based on athorough examination, his doctor recommends a course of botulinum type Ainjections to the bladder wall in combination with a SUDAFED® regimen.

The patient is injected with 200 U of botulinum type A divided among 30injections into the bladder wall. In addition, the patient ingests 2tablets of SUDAFED® each day. Within 7 days of receiving the injections,the patient reports the elimination of the incontinence symptoms.

Example 10

A 55 year old woman complains of incontinence at climax. She has notbeen diagnosed with any urological abnormality. Based on a thoroughexamination, her doctor recommends botulinum type A administration tothe bladder wall. Based on a thorough examination, her doctor recommendsa course of botulinum type A injections to the bladder wall incombination with a SUDAFED® regimen.

The patient is injected with 200 U of botulinum type A divided among 30injections into the bladder wall. In addition, the patient ingests 2tablets of SUDAFED® each day. Within 7 days of receiving the injections,the patient reports the elimination of the incontinence symptoms.

The bladder of the patient is instilled with a solution containing 1000U of botulinum type A by filling the bladder with the solution, allowingthe solution to remain within the bladder for 10 minutes, then drainingthe solution. Within 7 days of receiving the botulinum administration,the patient reports the elimination of the incontinence symptoms.

While this invention has been described with respect to various specificexamples and embodiments, it is to be understood that the invention isnot limited thereto and that it can be variously practiced with thescope of the following claims.

1. A method of treating incontinence associated with sexual activitycomprising administering a therapeutically effective amount of abotulinum toxin to the bladder of a patient in need thereof, therebytreating the incontinence associated with sexual activity.
 2. The methodof claim 1, wherein the botulinum toxin is selected from the groupconsisting of types A, B, C, D, E, and, G.
 3. The method of claim 2,wherein the botulinum toxin is type A or type B.
 4. The method of claim1, wherein the incontinence associated with sexual activity occursfollowing a surgical procedure for a prostate disorder.
 5. The method ofclaim 4, wherein the surgical procedure is selected from the groupconsisting of radical prostatectomy, laparoscopic radical prostatectomy,transurethral resection of the prostate, transurethral microwavetherapy, transurethral needle ablation, and cryosurgery.
 6. A method ofpreventing post-surgical incontinence associated with sexual activitycomprising administering a therapeutically effective amount of abotulinum toxin to the bladder of a patient, wherein the botulinum toxinis administered prior to the onset of incontinence.
 7. The method ofclaim 6, wherein the patient is administered the botulinum toxin at atime selected from the group consisting of before surgery, duringsurgery, after surgery, and combinations thereof.
 8. The method of claim7, wherein the patient is administered the botulinum toxin beforesurgery.
 9. The method of claim 7, wherein the patient is administeredthe botulinum toxin during surgery.
 10. The method of claim 8, whereinthe patient is further administered botulinum toxin after surgery.
 11. Amethod of treating incontinence associated with sexual activity in apatient previously diagnosed with a urogenic abnormality, comprisingadministering a therapeutically effective amount of a botulinum toxin toa patient in need thereof, thereby treating the incontinence associatedwith sexual activity.
 12. The method of claim 11, wherein the botulinumtoxin is selected from the group consisting of types A, B, C, D, E, and,G.
 13. A method of treating incontinence associated with sexual activitycomprising a) administering a therapeutically effective amount of abotulinum toxin to the bladder of a patient in need thereof, and; b)administering a therapeutically effective amount of an anitcholinergicdrug to a patient in need thereof; thereby treating the incontinenceassociated with sexual activity.
 14. The method of claim 13, wherein thebotulinum toxin is selected from the group consisting of types A, B, C,D, E, and, G.
 15. The method of claim 14, wherein the botulinum toxin istype A or type B.